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Abstract
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14–mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.
Highlights
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology
We show the functionality of sequence variants by bioinformatics and experimental support at gene and variant levels following the guidelines of the National Human Genome Research Institute[10]
Our study advances the field by identifying a pathogenic role for desmosomal dysfunction in EoE and the likely intersection of this dysfunction with calpain-14 and RhoGTPase–mediated pathways
Summary
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Eosinophilic esophagitis (EoE) is an emerging chronic allergic inflammatory esophageal disease clinically characterized by esophageal dysfunction; histologically by esophageal eosinophilia, epithelial hyperplasia, and dilated intercellular spaces (DIS) associated with impaired barrier function; and a high degree of heritability[1,2,3]. Mechanistic studies have substantiated that CAPN14 contributes to impaired epithelial barrier function, mediated in part by lost expression of desmoglein 1 (DSG1)[8], and that TSLP promotes adaptive type 2 T cell immunity associated with IL-5 and IL-13 overproduction[9]. Despite these advances, the causal gene variants and/or genomic networks for EoE pathogenesis remain unclear. We show the functionality of sequence variants by bioinformatics and experimental support at gene and variant levels following the guidelines of the National Human Genome Research Institute[10]
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